Cold Spring Harbor Molecular Case Studies最新文献_第10页

A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum. DYNC1H1的一种新变异可能与人类肌萎缩侧索硬化症-额颞叶痴呆谱系有关。

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-24 Print Date: 2022-02-01 DOI: 10.1101/mcs.a006096

Alexios-Fotios A Mentis, Dimitrios Vlachakis, Eleni Papakonstantinou, Ioannis Zaganas, George P Patrinos, George P Chrousos, Efthimios Dardiotis

{"title":"A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum.","authors":"Alexios-Fotios A Mentis, Dimitrios Vlachakis, Eleni Papakonstantinou, Ioannis Zaganas, George P Patrinos, George P Chrousos, Efthimios Dardiotis","doi":"10.1101/mcs.a006096","DOIUrl":"https://doi.org/10.1101/mcs.a006096","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) belongs to the ALS-frontotemporal dementia (FTD) spectrum and is hallmarked by upper and lower motor neuron degeneration. Here, we present a patient with a cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) pathogenic variant who fulfilled the ALS El Escorial criteria, and we review relevant literature. Using whole-exome sequencing, we identified a deleterious point variant in DYNC1H1 (c.4106A > G (p. Q1369R)) as a likely contributor to the ALS phenotype. In silico structural analysis, molecular dynamics simulation, and protein stability analysis predicted that this variant may increase DYNC1H1 protein stability. Moreover, this variant may disrupt binding of the transcription factor TFAP4, thus potentially acting as duon. Because (a) DYNC1H1 forms part of a ubiquitous eukaryotic motor protein complex, and (b) disruption of dynein function by perturbation of the dynein-dynactin protein complex is implicated in other motor neuron degenerative conditions, this variant could disrupt processes like retrograde axonal transport, neuronal migration, and protein recycling. Our findings expand the heterogenous spectrum of the DYNC1H1 pathogenic variant-associated phenotype and prompt further investigations of the role of this gene in ALS.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fe/9d/MCS006096Men.PMC8958913.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39427872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 10

Reanalysis of a novel variant in the IGF1R gene in a family with variable prenatal and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM-URDC (Undiagnosed Rare Disease Clinic) program. 一个具有可变产前和产后生长迟缓和畸形特征的家庭中IGF1R基因新变异的再分析:IUSM-URDC(未确诊罕见病诊所)计划的益处和可行性

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-24 Print Date: 2022-02-01 DOI: 10.1101/mcs.a006170

Annalise Jacobs, Catherine Burns, Purva Patel, Kayla Treat, Benjamin M Helm, Erin Conboy, Francesco Vetrini

{"title":"Reanalysis of a novel variant in the IGF1R gene in a family with variable prenatal and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM-URDC (Undiagnosed Rare Disease Clinic) program.","authors":"Annalise Jacobs, Catherine Burns, Purva Patel, Kayla Treat, Benjamin M Helm, Erin Conboy, Francesco Vetrini","doi":"10.1101/mcs.a006170","DOIUrl":"https://doi.org/10.1101/mcs.a006170","url":null,"abstract":"IGF1R-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 mo of age with a history of IUGR, poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole-exome sequencing revealed a novel c.1464T > G p.(Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in the URDC (Undiagnosed Rare Disease Clinic) and performed additional studies including deep phenotyping and familial segregation analysis, which demonstrated that the patient's IGF1R VUS was present in phenotypically similar family members. Furthermore, biochemical testing revealed an elevated serum IGF-1 level consistent with abnormal IGF-1 receptor function. Workup resulted in the patient's variant being upgraded from a VUS to likely pathogenic. Our report expands the variant and phenotypic spectrum of IGF1R-related disorders and illustrates benefits and feasibility of reassessing a VUS beyond the initial molecular diagnosis by deep phenotyping, 3D modeling, additional biochemical testing, and familial segregation studies through the URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/56/33/MCS006170Jac.PMC8958911.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39868558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Ethylmalonic encephalopathy masquerading as meningococcemia. 乙基丙二酸脑病伪装成脑膜炎球菌病。

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-24 Print Date: 2022-02-01 DOI: 10.1101/mcs.a006193

Ari Horton, Kai Mun Hong, Dinusha Pandithan, Meredith Allen, Caroline Killick, Stacy Goergen, Amanda Springer, Dean Phelan, Melanie Marty, Rebecca Halligan, Joy Lee, James Pitt, Belinda Chong, John Christodoulou, Sebastian Lunke, Zornitza Stark, Michael Fahey

{"title":"Ethylmalonic encephalopathy masquerading as meningococcemia.","authors":"Ari Horton, Kai Mun Hong, Dinusha Pandithan, Meredith Allen, Caroline Killick, Stacy Goergen, Amanda Springer, Dean Phelan, Melanie Marty, Rebecca Halligan, Joy Lee, James Pitt, Belinda Chong, John Christodoulou, Sebastian Lunke, Zornitza Stark, Michael Fahey","doi":"10.1101/mcs.a006193","DOIUrl":"https://doi.org/10.1101/mcs.a006193","url":null,"abstract":"Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in ETHE1 (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9d/aa/MCS006193Hor.PMC8958906.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39924099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

A novel TP53 tandem duplication in a child with Li–Fraumeni syndrome 一种新的TP53串联重复在儿童Li-Fraumeni综合征

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-01 DOI: 10.1101/mcs.a006181

Feng Xu, E. Aref-Eshghi, Jinhua Wu, J. Schubert, G. Wertheim, T. Bhatti, J. Pogoriler, Maha Patel, K. Cao, Ariel Long, Zhiqian Fan, E. Denenberg, Elizabeth A. Fanning, D. Wilmoth, Minjie Luo, L. Conlin, A. Dain, Sarah E Baldino, Kristin Zelley, N. Balamuth, S. MacFarland, Marilyn M. Li, Y. Zhong

{"title":"A novel TP53 tandem duplication in a child with Li–Fraumeni syndrome","authors":"Feng Xu, E. Aref-Eshghi, Jinhua Wu, J. Schubert, G. Wertheim, T. Bhatti, J. Pogoriler, Maha Patel, K. Cao, Ariel Long, Zhiqian Fan, E. Denenberg, Elizabeth A. Fanning, D. Wilmoth, Minjie Luo, L. Conlin, A. Dain, Sarah E Baldino, Kristin Zelley, N. Balamuth, S. MacFarland, Marilyn M. Li, Y. Zhong","doi":"10.1101/mcs.a006181","DOIUrl":"https://doi.org/10.1101/mcs.a006181","url":null,"abstract":"Li–Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single-nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy-number changes in TP53 are rare and account for <1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-seq) demonstrated the duplication was tandem, encompassing exons 2–6 and 28 nt of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nt is expected to result in a frameshift with a stop codon 18 codons downstream from the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy-number variants as well as SNVs/indels using NGS panels.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"1 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90642634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

m.3685T > C is a novel mitochondrial DNA variant that causes Leigh syndrome m.3685T > C是一种导致Leigh综合征的新型线粒体DNA变异

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-02-01 DOI: 10.1101/mcs.a006136

Jeffrey Jean, Eirini Christodoulou, Xiaowu Gai, B. Tamrazi, M. Vera, W. Mitchell, Ryan J. Schmidt

{"title":"m.3685T > C is a novel mitochondrial DNA variant that causes Leigh syndrome","authors":"Jeffrey Jean, Eirini Christodoulou, Xiaowu Gai, B. Tamrazi, M. Vera, W. Mitchell, Ryan J. Schmidt","doi":"10.1101/mcs.a006136","DOIUrl":"https://doi.org/10.1101/mcs.a006136","url":null,"abstract":"Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a 4-yr-old female who initially presented with generalized tonic–clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T2-weighted magnetic resonance imaging (MRI) revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T > C (MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient's condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T > C variant occurred de novo. The m.3685T > C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T > C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"57 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88457800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A mild case of sodium-dependent multivitamin transporter (SMVT) deficiency illustrating the importance of treatment response in variant classification 钠依赖性多维生素转运体(SMVT)缺乏症一例，说明治疗反应在变异分类中的重要性

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-02-01 DOI: 10.1101/mcs.a006185

Ingeborg Hauth, H. Waterham, R. Wanders, S. N. van der Crabben, C. V. van Karnebeek

{"title":"A mild case of sodium-dependent multivitamin transporter (SMVT) deficiency illustrating the importance of treatment response in variant classification","authors":"Ingeborg Hauth, H. Waterham, R. Wanders, S. N. van der Crabben, C. V. van Karnebeek","doi":"10.1101/mcs.a006185","DOIUrl":"https://doi.org/10.1101/mcs.a006185","url":null,"abstract":"Sodium-dependent multivitamin transporter (SMVT) deficiency is a recently described multivitamin-responsive inherited metabolic disorder (IMD) of which the phenotypic spectrum and response to treatment remains to be elucidated. So far, four pediatric patients have been described in three case reports with symptoms ranging from severe neurodevelopmental delay to feeding problems and failure to thrive, who demonstrated significant improvement after initiation of enhancement of targeted multivitamin treatment (biotin, pantothenic acid, and lipoic acid). We describe a fifth case of a patient presenting at the relatively mild end of the phenotypic spectrum with failure to thrive, frequent vomiting and metabolic acidosis with hypoglycemia, and mild osteopenia, who was diagnosed with SMVT deficiency due to compound heterozygous variants in SLC5A6. Additional genetic testing of variants of unknown significance (VUSs) as well as the clinical improvement in all aspects of the patient's disease upon initiation of treatment with biotin and pantothenic acid (plus lipoate as antioxidant) aided in the confirmation of this diagnosis. This case report aims to enhance recognition of the broad phenotypic spectrum of SMVT deficiency due to SLC5A6 mutations and discusses the different treatment strategies. It demonstrates how combining biochemical and genetic testing with the evaluation of (early) treatment response (i.e., using a “diagnostic therapeuticum”) can influence confirmation of pathogenicity of genomic variants.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"14 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86818245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

A case for newborn screening for pyridoxine-dependent epilepsy 新生儿吡哆醇依赖性癫痫筛查1例

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-02-01 DOI: 10.1101/mcs.a006197

C. Coughlin, Laura A Tseng, C. V. van Karnebeek

{"title":"A case for newborn screening for pyridoxine-dependent epilepsy","authors":"C. Coughlin, Laura A Tseng, C. V. van Karnebeek","doi":"10.1101/mcs.a006197","DOIUrl":"https://doi.org/10.1101/mcs.a006197","url":null,"abstract":"Pyridoxine-dependent epilepsy due to mutations in ALDH7A1 (PDH-ALDH7A1) is a highly treatable developmental and epileptic encephalopathy. Pharmacologic doses of pyridoxine are associated with dramatic clinical seizure improvement, and most patients achieve adequate seizure control with pyridoxine alone. Unfortunately, some patients with PDE-ALDH7A1 have died prior to when the diagnosis was made and subsequent treatment with pyridoxine could be implemented, highlighting the importance of a timely diagnosis. Although critical for seizure control, pyridoxine treatment alone is not sufficient for normal outcomes as most patients suffer intellectual and developmental delay. Adjunct lysine reduction therapies are associated with significant developmental improvements, although these treatments have limited efficacy if delayed after the first few months of life. Recently two biomarkers were identified that overcome previous technical hurdles for newborn screening. Herein we provide commentary that PDE-ALDH7A1 meets both current and historic criteria for newborn screening, and that a neonatal diagnosis and treatment can both reduce mortality from uncontrolled seizures and significantly improve the cognitive delay that is pervasive in this treatable disorder.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"115 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79403122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Patient perspective: my rare disease journey 病人视角:我的罕见病之旅

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-02-01 DOI: 10.1101/mcs.a006205

R. Alvarez

引用次数: 0

Toward transcriptomics as a primary tool for rare disease investigation 转录组学将成为罕见病研究的主要工具

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-02-01 DOI: 10.1101/mcs.a006198

S. Montgomery, J. Bernstein, M. Wheeler

{"title":"Toward transcriptomics as a primary tool for rare disease investigation","authors":"S. Montgomery, J. Bernstein, M. Wheeler","doi":"10.1101/mcs.a006198","DOIUrl":"https://doi.org/10.1101/mcs.a006198","url":null,"abstract":"In the past 5 years transcriptome or RNA-sequencing (RNA-seq) has steadily emerged as a complementary assay for rare disease diagnosis and discovery. In this perspective, we summarize several recent developments and challenges in the use of RNA-seq for rare disease investigation. Using an accessible patient sample, such as blood, skin, or muscle, RNA-seq enables the assay of expressed RNA transcripts. Analysis of RNA-seq allows the identification of aberrant or outlier gene expression and alternative splicing as functional evidence to support rare disease study and diagnosis. Further, many types of variant effects can be profiled beyond coding variants, as the consequences of noncoding variants that impact gene expression and splicing can be directly observed. This is particularly apparent for structural variants that disproportionately underlie outlier gene expression and for splicing variants in which RNA-seq can both measure aberrant canonical splicing and detect deep intronic effects. However, a major potential limitation of RNA-seq in rare disease investigation is the developmental and cell type specificity of gene expression as a pathogenic variant's effect may be limited to a specific spatiotemporal context and access to a patient's tissue sample from the relevant tissue and timing of disease expression may not be possible. We speculate that as advances in computational methods and emerging experimental techniques overcome both developmental and cell type specificity, there will be broadening use of RNA sequencing and multiomics in rare disease diagnosis and delivery of precision health.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"165 10 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86770441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Novel variants identified in CKAP2L in two siblings with Filippi syndrome. 在两个患有Filippi综合征的兄弟姐妹中发现了CKAP2L的新变异。

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-02-01 DOI: 10.1101/mcs.a006130

Ryan J Patrick, Jill Weimer, Laura Davis-Keppen, Megan L Landsverk

{"title":"Novel variants identified in CKAP2L in two siblings with Filippi syndrome.","authors":"Ryan J Patrick, Jill Weimer, Laura Davis-Keppen, Megan L Landsverk","doi":"10.1101/mcs.a006130","DOIUrl":"https://doi.org/10.1101/mcs.a006130","url":null,"abstract":"Pathogenic variants in CKAP2L have previously been reported in Filippi syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than 10 patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine), and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole-exome sequencing of the family identified a missense variant, c.2066G > A;p.(Arg689His), in trans with a frameshift variant, c.1169_1173del;p.(Ile390LysfsTer4), in CKAP2L To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2d/82/MCS006130Pat.PMC8958909.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10540628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0